Abstract 4139141: Predicted efficacy of inclisiran on cardiovascular outcomes in lower extremity peripheral artery disease: results of the In Silico Sirius study

Introduction: Symptomatic lower extremity peripheral artery disease (PAD) patients have the highest risk of cardiovascular (CV) outcomes among patients with established atherosclerotic cardiovascular disease (ASCVD). Inclisiran, an siRNA targeting PCSK9 mRNA, reduces LDL-C levels. In SIRIUS in silico trial (NCT05974345), inclisiran was predicted to lower CV events in ASCVD patients. Research question/Hypothesis: SIRIUS in silico study aims to predict the efficacy of inclisiran on CV outcomes in subgroups of patients with or without PAD. Methods: The SIRIUS in silico trial was conducted using a knowledge-based mechanistic computational model of ASCVD applied to a virtual ASCVD population with LDL-C ≥ 70 mg/dL. Each virtual patient is its own control. This model was previously calibrated and validated before running the trial. SIRIUS compared the efficacy of inclisiran vs placebo on top of High Intensity (HI) statins with or without ezetimibe on 3-Point-MACE defined as a composite of time to first occurrence of CV death, nonfatal myocardial infarction (MI) or nonfatal ischemic stroke (IS) over 5 years. Occurrence of major acute limb events (MALE) was also individually assessed in time-to-first-event analyses. Results: Among 204, 691 virtual SIRIUS ASCVD patients, 28,072 (13.7%) had PAD. At 5 years, the mean predicted percentage reduction in LDL-C with inclisiran as compared to placebo was -49.3% and -49.8% in patients with or without PAD, respectively. The predicted rate of 3P-MACE in the inclisiran arm was consistently lower than in the placebo arm in patients with PAD (17.62% vs 22.88%; Hazard Ratio (HR): 0.75 medium uncertainty) and in patients without PAD (10.33% vs 13.64%; HR: 0.75 low uncertainty). Compared to placebo, inclisiran was also predicted to consistently reduce MALE in patients with or without PAD (2.71% vs 4.11%; HR: 0.65 medium uncertainty and 0.19% vs 0.29%; HR: 0.66 high uncertainty respectively). Conclusion: Pending the results of ORION-4 and VICTORION-2-P, this first In Silico trial in virtual PAD patients predicted a potential effect of inclisiran on 3P-MACE and MALE reductions over 5 years follow-up.